Prof dr Nebojsa Radunovic
Sibenik 17.05.2014
• first generation of gonadotrophins, used
in the 1970’s, was human menopausal
gonadotrophin (hMG)
• produced from the urine of menopausal
women
• combination of follicle stimulating hormone
(FSH) and luteinizing hormone (LH) in a
1:1 ratio).
• first hMG was approved in the USA 1970, for
follicular development in anovulatory and
oligovulatory women (Nichols et al., 2001)
• It was obtained from urine of postmenopausal
women (contains both FSH and LH in high concentrations)
• Alternative to hMG became available in US 1987
in form of human urinary FSH largely purified of LH
and was still administered by the i.m. route.
• it remained mainstay of fertility treatment for almost 20 y
• Since 1980’s (second generation), a variety of
urinary gonadotrophins have been produced,
such as purified FSH(FSH-P) which contains
less than one international unit (IU) of LH per 75
IU of FSH
• Third generation of urinary gonadotrophins was
highly purified FSH (FSH-HP) with less than 0.1
IU of LH per 75 IU of FSH.
• Fourth generation of gonadotrophins was
produced using recombinant DNA technology
(rFSH), which is free from LH activity.
• Production of rFSH is independent of urine
collection, thus guaranteeing a high availability
of a biochemically pure FSH preparation that is
free from urinary protein contaminants.
• Process also yields FSH with minimal batch-tobatch discrepancy and low immunogenicity
which allows subcutaneous administration.
• The last decade of the 20th century witnessed a
potential milestone in the treatment of infertility as
previously urine derived gonadotrophins were
increasingly replaced by gonadotrophins produced
through recombinant technologies.
–
• These newer gonadotrophins are, however, more
expensive, especially since urinary gonadotrophins,
in principle, have come off patent protection and can
now be offered under generic pricing structures.
• More costly pricing, however, does not
necessarily indicate increased treatment
costs.
• If more expensive medications improve
treatment cycle outcomes, treatment cost
per established pregnancy may, indeed,
be unaffected or even reduced.
Prion transmission in blood and urine: what are implications
for recombinant and urinary derived gonadotrophins?
• Human Reproduction Vol.17, No.10 pp. 2501–2508, 2002
• Production of human menopausal and recombinant
gonadotrophin preparations for use in ovarian stimulation
protocols in fertility needs to ensure that safety of such
drugs remains as high as ever.
–
• Recombinant preparations utilize fetal calf serum or other
animal sera or proteins as part of a culture medium during
production.
• Human urinary-derived menotrophin preparations are
exposed to theoretical risk of infection from menopausal
donors of urine
Bye-bye urinary gonadotrophins? Recombinant FSH:
A real progress in ovulation induction and IVF?*
Norbert Gleicher, Mary Vietzke and Andrea Vidali
• Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• Recombinant gonadotrophin products do, indeed, represent
progress for routine ovulation induction and IVF cycles.
• Safety considerations favour recombinant products, while
overall outcome and cost considerations favour urinary
gonadotrophins.
• Outcome, appears to differ, based on age and ovarian function,
with younger patients benefiting from the FSH/LH combination
offered by urinary products, while older women and young
women with ovarian resistance, apparently benefting from
pure FSH stimulation.
Bye-bye urinary gonadotrophins? Recombinant FSH:
A real progress in ovulation induction and IVF?*
Norbert Gleicher, Mary Vietzke and Andrea Vidali
• Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• Young women with poor ovarian reserve may be best
stimulated with a pure FSH/ antagonist protocol.
• Conclusion: under current pricing structures in the US
recombinant gonadotrophins do not represent a major
progress for the treatments of ovulation induction and IVF.
• They, however, allow for an improved selectivity of stimulation
protocols.
• The creation of recombinant FSH/LH products and cost
adjustments for recombinant products, may affect these
conclusions in favour of recombinant products.
Impact of highly purified urinary FSH and recombinant FSH
on haemostasis: an open‐label, randomized, controlled trial
• Human Reproduction Volume 19, Issue 4 Pp. 838-848, 2004
• G. Ricci R. Simeone C. Pozzobon S. Guarnieri A. Sartore R. Pregazzi S.
Guaschino
• CONCLUSIONS:
• Ovarian stimulation with recombinant FSH does not influence
coagulation and fibrinolysis significantly, as already reported for
urinary gonadotrophins.
• The moderate changes induced by both treatments are no longer
detectable after 4 weeks.
• Several systematic reviews compared
recombinant gonadotrophin with urinary
gonadotrophins (HMG, purified FSH,
highly purified FSH) for ovarian
hyperstimulation in IVF and ICSI cycles
and these reported conflicting results.
• Each of these reviews used different
inclusion and exclusion criteria for trials
• An early systematic review (Daya 1995)
reported a higher clinical pregnancy rate
per cycle with FSH-P and FSH-HP when
compared with HMG
• A later review (Agrawal 2000) reported no
difference between these urinary
gonadotrophin products.
• Recombinant versus urinary
gonadotrophin for ovarian stimulation
in assisted reproductive technology
cycles
• Madelon van Wely, Irene Kwan, Anna L Burt, Jane Thomas, Andy
Vail, Fulco Van der Veen, Hesham G. Al-Inany
• To compare the effectiveness of
recombinant gonadotrophin (rFSH)
• with
• three main types of urinary
gonadotrophins (HMG, FSH-P & FSH-HP)
for ovarian stimulation
• in women undergoing IVF or ICSI
treatment cycles
• 42 trial included with total of 9606 couples.
• comparing rFSH to all other gonadotrophins
combined, irrespective of the down regulation
protocol used
• did not result in any evidence of statistically
significant difference in live birth rate
*(28 trials, 7339 couples)
• Differences were small. There was no proof of a
difference in live birth when comparing rFSH with
FSH-P or with FSH-HP.
• We may conclude that all these gonadotrophins are
equally effecive and safe, and that further trials are
unwaranted
• Differences were small. There was no proof of a
difference in live birth when comparing rFSH with
FSH-P or with FSH-HP.
• We may conclude that all these gonadotrophins are
equally effecive and safe, and that further trials are
unwaranted
Cost considerations
• of course, alone not determine which of the
gonadotrophin products are to be used in
preference.
• Principal determining factor in any medical
decision - making process is safety :
– to minimize potential risks
– to establish a risk / benefit ratio
Treatment decisions
• are consequence of evaluations
• sequential risk / benefit
&
• cost / benefit
• always represent compromises
Historical developments
• A final step in the purification of FSH was
achieved when in the mid-1990s, recombinant
FSH was introduced to the market.
• Recombinant (r)FSH is in its amino acid
sequence identical to human FSH, though
carbohydrate side chain attachments cause
pharmacodynamics, which do differ to some
extent from human pituitary FSH
– (Prevost, 1998).
Recombinant versus urinary gonadotrophin for ovarian
stimulation in assisted reproductive technology cycles
rFSH versus urinary gonadotrophins: primary
analyses, Outcome 1 Live birth (or ongoing
• pregnancy) by urinary gonadotrophin. . . . . . . .
. . . . . . . . . . . . . . . . . . 102
• Analysis 1.2. Comparison 1 rFSH versus
urinary gonadotrophins: primary analyses,
Outcome 2 Live birth (or ongoing
• pregnancy) by down regulation protocol. . . . . .
. . . . . . . . . . . . . . . . . . . 104
• Analysis 1.3. Comparison 1 rFSH versus
Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• There is, however, no convincing evidence that rFSH improves
clinical outcome in either standard ovulation induction or with IVF.
In fact, the opposite may be true and LH containing gonadotrophins
may have an outcome advantage, especially in younger women
with normal ovarian function, who undergo down-regulation with
GnRH-agonists.
• Since outcome affects cost to a large degree, the lower acquisition
costs of urinary products represent a very signicant factor in
choosing a preferred medication
Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• There is, however, no convincing evidence that rFSH improves
clinical outcome in either standard ovulation induction or with IVF.
In fact, the opposite may be true and LH containing gonadotrophins
may have an outcome advantage, especially in younger women
with normal ovarian function, who undergo down-regulation with
GnRH-agonists.
• Since outcome affects cost to a large degree, the lower acquisition
costs of urinary products represent a very signicant factor in
choosing a preferred medication
• Several systematic reviews compared
recombinant gonadotrophin with urinary
gonadotrophins (HMG, purified FSH, highly
purified FSH) for ovarian hyperstimulation in IVF
and ICSI cycles and these reported conflicting
results. Each of these reviews used different
inclusion and exclusion criteria for trials. Our aim
in producing this review was to bring together all
randomised studies in this field under common
inclusion criteria with consistent and valid
statistical methods.
• We included 42 trials with a total of 9606 couples.
Comparing rFSH to all other gonadotrophins combined,
irrespective of the down-regulation protocol used, did not
result in any evidence of a statistically significant difference
in live birth rate (28 trials, 7339 couples, odds ratio (OR)
0.97, 95% CI 0.87 to 1.08). This suggests that for a group
with a 25% live birth rate using urinary gonadotrophins the
rate would be between 22.5% and 26.5% using rFSH. There
was also no evidence of a difference in the OHSS rate (32
trials, 7740 couples, OR 1.18, 95% CI 0.86 to 1.61). This
means that for a group with 2% risk of OHSS using urinary
gonadotrophins, the risk would be between 1.7% and 3.2%
using rFSH.
• When different urinary gonadotrophins were
considered separately, there were significantly
fewer live births after rFSH than HMG (11 trials,
N=3197, OR 0.84, 95% CI 0.72 to 0.99). This
means that for a live birth rate of 25% using
HMG, use of rFSH instead would be expected to
result in a rate between 19% and 25%. There was
no evidence of a difference in live births when
rFSH was compared with FSH-P (5 trials, N=1430,
OR 1.26, 95% CI 0.96 to 1.64) or when rFSH was
compared with FSH-HP (13 trials, N=2712; OR
1.03, 95% CI 0.86 to 1.22).
• Clinical choice of gonadotrophin should
depend on availability, convenience and costs.
Differences between urinary gonadotrophins
were considered unlikely to be clinically
significant.
• Further research on these comparisons is
unlikely to identify substantive differences in
effectiveness or safety.
• This suggests that for a group with a 25% live
birth rate using urinary gonadotrophins would be
between 22.5% and 26.5% using rFSH. There
was also no evidence of a difference in the
OHSS rate (32 trials, 7740 couples, OR 1.18,
95% CI 0.86 to 1.61). This means that for a
group with 2% risk of OHSS using urinary
gonadotrophins, the risk
• would be between 1.7% and 3.2% using rFSH.
• When different urinary gonadotrophins were
considered separately, there were significantly
fewer live births after rFSH than HMG (11
SUMMARY
• Recombinant FSH versus urinary gonadotrophins (HMG,
purified FSH, highly purified FSH) for ovarian
hyperstimulation in IVF and ICSI cycles
• Several systematic reviews compared recombinant FSH
with urinary gonadotrophins (HMG, purified FSH, highly
purified FSH) for ovarian hyperstimulation in IVF and
ICSI cycles and these reported conflicting results.
• We included 42 trials with in total 9606 couples.
Comparing rFSH with urinary gonadotrophins overall did
not result in any difference in live birth rate, OHSS or any
of the other outcomes. Comparing rFSH with HMG/HPHMG resulted in a significantly lower live birth rate in the
rFSH group though differences were small. There was
no proof of a difference in live birth when comparing
SUMMARY
• Recombinant FSH versus urinary gonadotrophins (HMG,
purified FSH, highly purified FSH) for ovarian
hyperstimulation in IVF and ICSI cycles
• Several systematic reviews compared recombinant FSH
with urinary gonadotrophins (HMG, purified FSH, highly
purified FSH) for ovarian hyperstimulation in IVF and
ICSI cycles and these reported conflicting results. We
included 42 trials with in total 9606 couples. Comparing
rFSH with urinary gonadotrophins overall did not result in
any difference in live birth rate, OHSS or any of the
• other outcomes. Comparing rFSH with HMG/HP-HMG
resulted in a significantly lower live birth rate in the rFSH
group though differences were small. There was no
proof of a difference in live birth when comparing rFSH
Prion transmission in blood and urine: what are implications
for recombinant and urinary derived gonadotrophins?
• Human Reproduction Vol.17, No.10 pp. 2501–2508, 2002
• Production of human menopausal and recombinant
gonadotrophin preparations for use in ovarian stimulation
protocols in fertility needs to ensure that safety of such
drugs remains as high as ever.
–
• Recombinant preparations utilize fetal calf serum or other
animal sera or proteins as part of a culture medium during
production.
• Human urinary-derived menotrophin preparations are
exposed to theoretical risk of infection from menopausal
donors of urine
Bye-bye urinary gonadotrophins? Recombinant FSH:
A real progress in ovulation induction and IVF?*
Norbert Gleicher, Mary Vietzke and Andrea Vidali
• Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• Recombinant gonadotrophin products do, indeed, represent
progress for routine ovulation induction and IVF cycles.
• Safety considerations favour recombinant products, while
overall outcome and cost considerations favour urinary
gonadotrophins.
• Outcome, appears to differ, based on age and ovarian function,
with younger patients benefiting from the FSH/LH combination
offered by urinary products, while older women and young
women with ovarian resistance, apparently benefting from
pure FSH stimulation.
Bye-bye urinary gonadotrophins? Recombinant FSH:
A real progress in ovulation induction and IVF?*
Norbert Gleicher, Mary Vietzke and Andrea Vidali
• Human Reproduction Vol.18, No.3 pp. 476±482, 2003
• Young women with poor ovarian reserve may be best
stimulated with a pure FSH/ antagonist protocol.
• Conclusion: under current pricing structures in the US
recombinant gonadotrophins do not represent a major
progress for the treatments of ovulation induction and IVF.
• They, however, allow for an improved selectivity of stimulation
protocols.
• The creation of recombinant FSH/LH products and cost
adjustments for recombinant products, may affect these
conclusions in favour of recombinant products.
Impact of highly purified urinary FSH and recombinant FSH
on haemostasis: an open‐label, randomized, controlled trial
• Human Reproduction Volume 19, Issue 4 Pp. 838-848, 2004
• G. Ricci R. Simeone C. Pozzobon S. Guarnieri A. Sartore R. Pregazzi S.
Guaschino
• CONCLUSIONS:
• Ovarian stimulation with recombinant FSH does not influence
coagulation and fibrinolysis significantly, as already reported for
urinary gonadotrophins.
• The moderate changes induced by both treatments are no longer
detectable after 4 weeks.